Originally published as JCO Early Release 10.1200/JCO.2005.01.917 on September 6 2005

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Phase I Pharmacokinetic Study of S-1 Plus Cisplatin in Patients With Advanced Gastric Carcinoma

From the Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Taiho Pharma USA, Inc, Princeton, NJ

Address reprint requests to Jaffer A. Ajani, MD, The University of Texas M.D. Anderson Cancer Center, Box 426, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: jajani{at}mdanderson.org

	ABSTRACT

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PURPOSE: The conversion rate of tegafur (a component of S-1) to fluorouracil (FU) differs in Asians and whites because of polymorphic differences in the CYP2A6 gene. S-1 with cisplatin is considered highly active in Japanese gastric cancer patients. Therefore, we initiated a phase I pharmacokinetic study of this combination in our gastric cancer patients.

PATIENTS AND METHODS: Patients received cisplatin intravenously on day 1 and S-1 orally, twice daily, on days 1 to 21 every 28 days. At level 1, the S-1 dose was 25 mg/m²/dose (50 mg/m²/d), but it was increased by 5 mg/m²/dose for the next level. Cisplatin was administered at 75 mg/m² (for levels 1 and 2) but was then reduced to 60 mg/m² (level 1A). At every level, a cohort of three patients, which could be expanded to six patients, was studied. Maximum-tolerated dose (MTD) was determined based on the dose-limiting toxicity (DLT) in the first cycle. Patients with histologic proof of gastric adenocarcinoma and near-normal organ function were studied.

RESULTS: Sixteen patients were enrolled. No DLTs occurred at level 1. However, DLTs occurred at levels 2 and 1A. The area under the curve for FU correlated significantly with DLT (P = .006) and grade 3 to 4 diarrhea (P = .004). Six partial responses were confirmed, including three at the MTD.

CONCLUSION: At the established MTD of S-1 plus cisplatin, the S-1 dose (50 mg/m²/d for 21 days) is lower in our study than in the Japanese study (80 mg/m²/d for 21 days). A multi-institutional phase II study of this active combination is currently accruing patients.

	INTRODUCTION

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There is considerable interest in S-1, which is a fourth-generation oral fluoropyrimidine that is a formulation of tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) at a molar ratio of 1:0.4:1.¹ S-1 is a unique compound that exemplifies the future of oral cytotoxic drug engineering. FT is the prodrug for cytotoxic fluorouracil (FU), and CDHP prevents its degradation. The addition of Oxo to CDHP and FT to form S-1 is a novel approach. It is conceptually appealing and, in animal models, Oxo is protective against FT-induced diarrhea.^2,3 The protective value of Oxo against FT-induced diarrhea in humans is not yet established. A planned pharmacokinetic (PK) study of FT plus CDHP would shed light on this issue. The diarrheagenic property of FU is a result of its phosphorylation in the intestine primarily by orotate phosphoribosyltransferase (OPRT). Oxo is a specific inhibitor for OPRT. Thus, the protective effect of Oxo is from its ability to reduce phosphorylation of FU; however, FU can also be phosphorylated by uridine phosphorylase or thymidine phosphorylase, generating 5-fluorodeoxyuridine monophosphate and thus resulting in diarrhea. CDHP is a potent and competitive inhibitor of dihydropyrimidine dehydrogenase and, thus, reduces the degradation of FU and allows its higher concentrations to enter the anabolic pathway.⁴ PK studies of S-1 have demonstrated substantial prolongation of the half-life of FU.⁵ Thus, one component of S-1, CDHP, reduces the degradation of cytotoxic FU, and another component, Oxo, potentially reduces its GI toxicity.

A number of studies have reported activity of S-1 as a single agent against gastric cancer,^6-8 with response rates ranging from 26% to 45%. Additionally, a 76% response rate was reported in one Japanese study of 25 patients when S-1 was combined with cisplatin.⁹ The dose of S-1 in this Japanese study was 80 mg/m²/d for 21 days; however, the same dose may not be tolerated by Western patients for of a number reasons.

FT is converted to FU in the liver by cytochrome P450 (CYP) enzyme. FT is hydroxylated to 5'-hydroxytegafur and eventually converted to FU.¹⁰ CYP2A6 of the CYP family is now identified as the principal enzyme responsible for this conversion process.¹¹ However, different polymorphisms in the CYP2A6 gene among Asians and whites, which affect its efficacy in the rate of conversion of FT to FU, have been identified.^12-14 In addition, CYP2A6 is also thought to be responsible for nicotine metabolism, and differences in the expressed isoforms seem to reduce smoking-related lung cancer rates in Latinos and Asians compared with whites,¹⁵ thus substantiating the importance of polymorphic changes. With due considerations to these facts and also noting that the combination of S-1 with cisplatin has not been studied in the West, we performed a phase I PK study in Western patients to determine the maximum-tolerated dose (MTD) to be investigated further in a multi-institutional phase II trial.

	PATIENTS AND METHODS

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Eligibility
All patients with advanced, unresectable, histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction were eligible if they were 18 years of age and had a Karnofsky performance score of 70, a life expectancy of 12 weeks, an absolute granulocyte count of more than 1,500/µL, a platelet count of more than 100,000/µL, a hemoglobin level of more than 9.0 g/dL, a serum bilirubin level of less than 1.5 x the upper limit of normal (ULN), and a normal creatinine level. Patients also were required to have transaminases less than 2.5 x the ULN (< 5 x the ULN in case of liver metastases). Presence of measurable cancer was not a requirement. Only patients who could swallow tablets were eligible. All patients were told to practice medically effective contraception. A written informed consent was required. Patients were excluded if they had brain metastases, had severe comorbid conditions, or lacked the ability to comply. Patients receiving concurrent inducers or inhibitors of enzyme CYP2A6 were excluded.

Pretreatment Evaluations
The baseline evaluations included history, complete physical examination, urine pregnancy test, Karnofsky performance status, CBC count, serum chemistries and electrolytes, urinalysis, chest x-ray, and recording of concomitant medications. In addition to these evaluations, imaging studies (computed tomography or magnetic resonance imaging) were performed.

Definitions and Treatment Scheme
The dose-limiting toxicity (DLT) was defined, based on the drug-related toxicity according to the National Cancer Institute Common Toxicity Criteria version 2.0, during the first cycle as grade 3 or higher nonhematologic toxicity (excluding controlled nausea and/or vomiting, hyper bilirubinemia without AST or ALT increase, and clinical liver function failure), grade 4 hematologic toxicity, or febrile neutropenia. If more than two patients in a given cohort experienced DLT, then that dose level was to be declared intolerable. Thus, the MTD was defined as the highest dose level at which less than 33% of the patients experienced a DLT. A dose escalation of S-1 was made if no DLT was seen in a cohort of three patients, and if DLT was seen in one patient, the cohort was expanded to six patients, with the MTD declared if two or more patients experienced a DLT. At level 1, the dose of S-1 was 25 mg/m²/dose twice daily (50 mg/m²/d). At level 2, the dose of S-1 was 30 mg/m²/dose (60 mg/m²/d), and subsequently, the dose of S-1 was to be increased by 5 mg/m²/dose. The dose of cisplatin was to be kept constant at 75 mg/m²; however, it was reduced to 60 mg/m² for safety reasons to create level 1A.

Patients received S-1 orally twice daily from day 1 to day 21 of each 28-day cycle. S-1 was administered at least 1 hour before or after a meal. S-1 was held if a DLT occurred and reduced if resumed in the subsequent cycle. Compliance and drug accountability were thoroughly scrutinized by asking patients to keep a daily diary tracking S-1 and all other medications. A self-scored daily calendar of toxicities was reviewed with each patient at the end of each cycle (Fig 1).

View larger version (96K): [in this window] [in a new window]   Fig 1. One of four self-scored toxicity sheets by a patient on S-1 plus cisplatin. IV, intravenous; ICU, intensive care unit; TPN, total parenteral nutrition.

Evaluation During Therapy
CBC count and serum chemistries were monitored periodically during therapy. Response to therapy was assessed after the first cycle of the combination. All partial or complete responses were confirmed for a minimum of 4 weeks; otherwise, responses were assessed every two cycles. Therapy was discontinued in case of progression of cancer, unacceptable toxicity, or consent withdrawal.

Response and Toxicity Criteria
Response Evaluation Criteria in Solid Tumors criteria were used to assess response to S-1 plus cisplatin, and National Cancer Institute Common Toxicity Criteria version 2.0 were used to assess toxicity. Because this study involved two agents, dose adjustments were made for each agent if a distinction in toxicity could be made. If both agents were felt to be causing the toxicity, dose reduction was performed for both drugs. S-1 dose modification was to be made in the following two ways: during a 4-week cycle and at the initiation of subsequent cycle. In case of a related grade 3 or 4 toxicity during therapy, S-1 was held and resumed at a reduced dose (5 mg/m²/dose) when toxicity resolved, and the reduce dose was used for subsequent cycles. Cisplatin was also reduced by 25% for the subsequent cycle in case of a related grade 3 or 4 toxicity. Drug doses were never increased.

PK Methods
Serial blood samples in relation to the timing of the S-1 dose were collected on days 1 (before S-1, and 0.5, 1, 2, 4, 8, and 12 hours after S-1), 8, 15, and 21 (morning before S-1 trough sample and 2 hours after S-1) during the first cycle of protocol therapy. PK analysis was performed on the plasma concentrations of the S-1 components (FT, CDHP, and Oxo) and its metabolites (FU and cyanuric acid [CA]) for day 1. Plasma concentrations of all compounds were determined using a liquid chromatographic-tandem mass spectrometry (LC/MS/MS), based on the methods of Mastushima et al.¹⁶

Analysis of FT, FU, CDHP, and CA was conducted according to the following methods. An aliquot of plasma with their internal standard and 0.5 mol/L of phosphate buffer (pH = 2) was extracted with ethylacetate. The pentafluorobenzyl bromide derivatives were prepared. The derivatives, constituted in methanol, were injected into the LC/MS/MS. For the determination of Oxo, the plasma with the internal standard and 0.1 mol/L of ammonium acetate buffer (pH = 4.2) was extracted by solid-phase extraction cartridges (Bond Elut NH2 column[100mg, 1cc]; Varian Inc, Palo Alto, CA). The elution from solid-phase extraction was decomposed by HCl and formed pentafluorobenzyl bromide derivative. The derivative, constituted in methanol, was injected into the LC/MS/MS. For the analysis of all compounds by the API 3000 (LC/MS/MS system; MDS Sciex, Concord, Ontario, Canada), ¹⁵N₂-FU, ¹³C₃,¹⁵N-CDHP, 1,3-¹⁵N₂-uracil, ¹³C,¹⁵N-oxonate, and ¹⁵N₃-CA were used for internal standards. The lower limits of quantification of FT, FU, CDHP, Oxo, and CA were 10, 1, 2, 1, and 8 ng/mL, respectively. The mean coefficients of determination of FT, FU, CDHP, Oxo, and CA were 0.9894, 0.9940, 0.9930, 0.9945, and 0.9963 ng/mL, respectively.

From the plasma concentration data, PK parameters (area under the curve [AUC], 0 to 12) and maximum concentrations (C_max) were derived for analyzed data using noncompartmental methods with WINNonlin (Scientific Consultant, Apex, NC) Professional Version 3.1 (Pharsight Corp, Mountain View, CA) or later versions. Patients with partial data were evaluated on a case-by-case basis to determine whether sufficient data were available for a meaningful analysis. We derived the area under the multiple-dose plasma concentration–time curve for time 0 to the last quantifiable time point (12 hours; AUC_0-12). AUCs_0-12 were also computed by the linear trapezoidal method, including measured single-dose plasma C_max and first time of the sample in which C_max was measured.

	RESULTS

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Patient Population
A total of 16 patients were recruited onto the study. One patient (patient 7) at level 1 was excluded from the MTD determination and PK analyses because she inadvertently took only half of the prescribed twice-daily dose of S-1 during the first cycle. Another patient was recruited in her place. The patient characteristics are listed in Table 1. Only 25% of patients had prior systemic chemotherapy. Three patients had received chemotherapy for advanced gastric cancer, and one patient had received chemotherapy in the preoperative setting. No patients received chemotherapy in the adjuvant setting. Only two patients had a gastrectomy before enrollment.

PKs and Pharmacodynamics
Plasma samples for PK studies were obtained from all 16 patients (15 eligible patients and one ineligible patient). The predose (trough) and 2-hour postdose (C_max in steady-state) plasma concentrations on days 8, 15, and 21 were plotted graphically as an indicator of the time required to reach a steady-state (Fig 2). At all dose levels, FU concentrations on days 8, 15, and 21 were similar to each other; therefore, FU concentration in plasma reached a steady-state on day 8. PK parameters on day 1 for FT, FU, CDHP, Oxo, and CA at each dose level are listed in Table 3. FU, the active metabolite of FT, readily appeared in plasma, and the mean values for C_max and AUC_0-12 increased according to S-1 dose. However, neither coadministration of cisplatin nor the cisplatin dose affected the FU C_max and AUC.

View larger version (19K): [in this window] [in a new window]   Fig 2. The dose-dependent maximum concentration and area under the curve of fluorouracil (FU) at three dose levels of S-1 and cisplatin.

View larger version (13K): [in this window] [in a new window]   Fig 3. Spearman's correlation between area under the curve of fluorouracil and the occurrence of dose-limiting toxicities (DLTs) at various dose levels.

View larger version (11K): [in this window] [in a new window]   Fig 4. Correlation between severe diarrhea and the area under the curve of fluorouracil (FU), potassium oxonate (Oxo), and cyanuric acid (CA).

	DISCUSSION

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In the comparable dose range of S-1, the AUC of FU (Table 4) seems higher in white patients than in Japanese patients.^5,17,18 It is postulated that the efficacy of CYP2A6 enzyme is higher in whites than in Asians. This would cause whites to convert FT to FU at a faster rate, thus achieving a higher AUC of FU than Asians (Table 4). This notion is further substantiated by the results of the AUC of FT in Asians who accumulate FT and achieve a higher AUC than whites who convert FT relatively rapidly and achieve a lower AUC (Table 5). These differences in the metabolism of FT are attributed to polymorphic changes in the CYP2A6 gene.^12-14 The differences in the AUC of FU are not so striking with uracil + FT¹⁹ compared with S-1 between Americans and Japanese because uracil compared with CDHP is not a potent inhibitor of dihydropyrimidine dehydrogenase enzyme, thus allowing more rapid catabolism of FU and less accumulation. The lower AUC of FU at higher doses of S-1 may be responsible for the reported better tolerance of S-1 by Japanese compared with whites. The toxicity of S-1 is directly correlated with S-1 dose in Asian patients. In Japanese patients, the S-1 dosing is narrow (30 to 40 mg/m²/dose twice daily) in phase II studies,^7,8 and the AUC of FT correlates with the dose of S-1.

The encouraging response rate resulting from S-1 plus cisplatin reported from Japan⁹ led us to pursue this combination, but we were also interested in PKs. In the current study, the AUC of FU at an S-1 dose of 25 mg/m² was 554 ± 261 ng x hr/mL; this was similar to the AUC observed in a European study at the same daily dose of S-1,⁵ which was reported to be 589 ng x hr/mL (271.5 µmol/L x min; FU molecular weight = 130.1). This may indirectly suggest that the addition of cisplatin does not affect the PK of FU. Koizumi et al,⁹ in a study of Japanese patients, also observed no significant differences in the PKs of various S-1 components with or without cisplatin.

Oxo inhibits OPRT, the enzyme that phosphorylates FU in the GI tract; thus, the inhibition of OPRT can theoretically result in the prevention of diarrhea.² However, Oxo is metabolized to CA in the gastric juice. Peters et al²⁰ have reported that food intake affected the PK of only Oxo but not FU, FT, or CDHP. The food to fast ratio was 0.48 for the AUC of Oxo (P < .0005) and 5.1 for the AUC of CA (P = .019). Thus, if Oxo is truly effective in reducing diarrhea, could the differences be related to the intake of S-1 in relation to a meal? Unfortunately, the data are not clear. In the previous North American study, patients took S-1 1 hour within a meal, and the AUCs of Oxo were 232 ng x hr/mL (for 30 mg/m²/dose), 206 ng x hr/mL (for 35 mg/m²/dose), and 485 ng x hr/mL (for 40 mg/m²/dose). However, in the current study, the mean AUCs of Oxo were 360 ng x hr/mL (for 25 mg/m²/dose) and 380 ng x hr/mL (for 30 mg/m²/dose). The mean Oxo levels in the current study are comparable to the Oxo AUCs observed in Japanese patients at the recommended S-1 dose of 36 mg/m²/dose as average (range, 32 to 40 mg/m²/dose).

FU PKs have been significantly correlated with the occurrence of severe diarrhea as a result of S-1.^5,18 We found that there were significant correlations between the AUC of FU or CA and the occurrence of severe diarrhea (FU, P = .004; CA, P = .02; Fig 4), but as one would expect, the correlation was not significant for the AUC of Oxo (P = .158; Fig 4). The protective action of Oxo occurs in the intestinal tract, but if Oxo is metabolized rapidly (therefore, resulting in high AUC of CA), then its effectiveness against diarrhea would be less. Therefore, it may be important to exploit methods to reduce the metabolism of Oxo in the GI tract (example, relationship of S-1 dosing with meals). Should the patient experiencing significant diarrhea from S-1 not be administered more Oxo? The answer to this question is not known. Another question is whether a useful clinical strategy can be developed to assess the risk of toxicity from S-1. It may be possible to study polymorphism in the CYP2A6 gene to predict toxicity as well as to assess the single-dose PK to measure FU levels before chronic administration of S-1. The utility of these approaches has not been established.

Our experience and the experience of others suggest that oral agents can be used in the treatment of gastric carcinoma, as in other GI malignancies. Because most of these agents are absorbed in the small intestine, gastrectomy does not seem to influence the PK of fluoropyrimidines.¹⁷ In our study, only two patients had prior gastrectomy, and we found no differences in the PK of FU and Oxo.

In conclusion, the MTD of the S-1 and cisplatin combination (S-1 25 mg/m²/dose administered twice daily on days 1 through 21 and cisplatin 75 mg/m² on day 1) for Western patients has been defined. A direct correlation was observed between the AUC of FU and DLT, as well as severe diarrhea. This study confirms that the dose of S-1 tolerated by Western patients is lower than the dose tolerated by Japanese patients. This is most likely related to previously described polymorphic differences in the key CYP2A6 gene. A phase II multicenter study of S-1 with cisplatin is now accruing patients.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Jaffer A. Ajani Taiho Pharmaceutical Co Ltd (A) Taiho Pharmaceutical Co Ltd (B) Taiho Pharmaceutical Co Ltd (C) Kazumasa Ikeda Taiho Pharmaceutical Co Ltd Hiroshi Anbe Taiho Pharmaceutical Co Ltd Michele Houghton Taiho Pharmaceutical Co Ltd Peter Urrea Taiho Pharmaceutical Co Ltd

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Acknowledgment

 
We thank Lukas Makris and John Ilgenfritz for data analysis at BioCor, Yardley, PA.

	NOTES

 
Supported by a grant from Taiho Pharma USA, Inc, Princeton, NJ.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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3. Takechi T, Nakano K, Uchida J, et al: Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur, in experimental tumor models in rats. Cancer Chemother Pharmacol 39:205-211, 1997[CrossRef][Medline]

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5. van Groeningen CJ, Godefridus J, Peters J, et al: Phase I clinical and pharmacokinetic study of S-1 in advanced solid tumors. J Clin Oncol 18:2772-2779, 2000[Abstract/Free Full Text]

6. Chollet P, Schoffski P, Weigang-Kohler K, et al: Phase II trial with S-1 in chemotherapy-naive patients with gastric cancer: A trial performed by the EORTC Early Clinical Studies Group (ECGS). Eur J Cancer 39:1264-1270, 2003

7. Sakata Y, Ohtsu A, Horikoshi N, et al: Late phase II study of novel oral fluoropyrimidine anticancer drug S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium) in advanced gastric cancer patients. Eur J Cancer 34:1715-1720, 1998

8. Koizumi W, Kurihara M, Nakano S, et al: Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced gastric cancer. Oncology 58:191-197, 2000[CrossRef][Medline]

9. Koizumi W, Tanabe S, Saigenji K, et al: Phase I/II study of S-1 combined with cisplatin in patients with advanced gastric cancer. Br J Cancer 89:2207-2212, 2003[CrossRef][Medline]

10. El-Sayed YM, Sadee W: Metabolic activation of ftorafur [R,S-1-(tetrahyro-2-furanyl)-5-fluorouracil]: The microsomal oxidative pathway. Biochem Pharmacol 31:3006-3008, 1982[CrossRef][Medline]

11. Ikeda K, Yoshisue K, Matsushima E, et al: Bioactivation of tegafur to 5-fluorouracil is catalyzed by cytochrome P-450 2A6 in human liver microsomes in vitro. Clin Cancer Res 6:4409-4415, 2000[Abstract/Free Full Text]

12. van der Weide J, Steijns LS: Cytochrome P450 enzyme system: Genetic polymorphisms and impact on clinical pharmacology. Ann Clin Biochem 36:722-729, 1999

13. Yoshida R, Nakajima M, Nishimura K, et al: Effects of polymorphism in promoter region of human CYP2A6 gene (CYP2A6*9) on expression level of messenger ribonucleic acid and enzymatic activity in vivo and in vitro. Clin Pharmacol Ther 74:69-76, 2003[CrossRef][Medline]

14. Daigo S, Takahashi Y, Fujieda M, et al: A novel mutant of the CYP2A6 gene (CYP2A6*11) found in a cancer patient who showed poor metabolic phenotype towards tegafur. Pharmacogenetics 12:299-305, 2002[CrossRef][Medline]

15. Benowitz NL, Perez-Stable EJ, Herrera B, et al: Slower metabolism and reduced intake of nicotine from cigarette smoking in Chinese-Americans. J Natl Cancer Inst 94:108-115, 2002[Abstract/Free Full Text]

16. Matsushima E, Yoshida K, Kitamura R, et al: Determination of S-1 (combined drug of tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate) and 5-fluorouracil in human plasma and urine using high-performance liquid chromatography and gas chromatography-negative ion chemical ionization mass spectometry. J Chromatogr B Biomed Sci Appl 691:95-104, 1997[CrossRef][Medline]

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18. Hoff PM, Saad ED, Ajani JA, et al: Phase I study with pharmacokinetics of S-1 on an oral daily schedule for 28 days in patients with solid tumors. Clin Cancer Res 9:134-142, 2003[Abstract/Free Full Text]

19. Shirao K, Hoff PM, Ohtsu A, et al: Comparison of the efficacy, toxicity, and pharmacokinetics of a uracil/tegafur (UFT) plus oral leucovorin (LV) regimen between Japanese and American patients with advanced colorectal cancer: Joint United States and Japan study of UFT/LV. J Clin Oncol 22:3466-3474, 2004[Abstract/Free Full Text]

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Submitted October 4, 2004; accepted December 28, 2004.

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